The liver is a major source of the plasma lipoproteins. The liver secretes the very low density lipoproteins (VLDL) and the nascent high density lipoprotein (HDL). Variation in the plasma lipoprotein levels which occur in hormonal imbalance, dietary variations or various disease states is largely under control of the liver. With increasing interest in HDL because of the apparent inverse relationship between plasma HDL concentrations and risk of atherosclerosis, it is important to examine in detail the regulation of HDL production. We will use the isolated perfused rat liver for our studies, and will examine several hormonal and nutritional conditions which we have shown either to stimulate or reduce VLDL production. The stimulatory conditions to be examined include availability of free fatty acids, modified by fatty acid structure and quantity, the fed state, estrogen administration to the liver donor, and hypothyroidism; while conditions which reduce VLDL production which we will examine include the fasting state, experimental diabetes, and hyperthyroidism. Since the HDL levels are higher in females, associated with a lower risk of heart disease than for males, we will compare hepatic formation of HDL by livers of male and female rats. Immunochemical assays for the various apoproteins will be used to assist in the evaluation of HDL production by livers under these various conditions. Assessment of apoprotein distribution isoelectric focusing will be routinely used. Lipid analyses will be used to complement the apoprotein determinations in our assessment of HDL (and VLDL) production by the liver. An understanding of HDL production and composition will provide valuable information with regard to regulation of plasma lipid and lipoprotein levels and perhaps help provide a more rational means for prevention, control and treatment of atherosclerosis.